DESCRIPTION (Applicant's Abstract): The long-term objective of this project is to develop antibody-based medications for the treatment of abuse of synthetic stimulants like methamphetamine (METH). A treatment is badly needed since repeated use of these drugs can lead to cardiovascular problems, severe depression, psychosis, and violent behavior. These new medications could be used in a treatment plan for a recovering addict or in an emergency room setting for rapidly reversing a drug overdose. The experiments in this proposal are designed to systematically test the hypothesis that monoclonal antibodies (MAb) and their antigen binding fragments (Fab) could be used to treat a range of medical problems associated with stimulant abuse. Although the eventual goal is to select a MAb that could be used for treating all of the METH-like synthetic stimulants, the main focus of the project will be on METH. Therefore, high affinity MAb against METH will be selected, and 200-400 g of monoclonal anti-METH IgG will be generated in a non-mammalian bioreactor. After production and purification of the IgG and Fab, preclinical testing will begin. To assess the potential use antibodies for treating addiction, a comprehensive series of studies following active and passive immunization (with the monoclonal IgG) will be conducted in a rat model of human "binge" drug use. These studies will include the behavioral evaluation of the effectiveness of immunotherapy after repeated METH doses over an extended period of time. For evaluating the use of anti-METH Fab for treating overdose, an integrated series of pharmacokinetic, behavioral and neurochemical studies after various types of treatments will be conducted. Finally, the pharmacokinetic and behavioral effects of the anti-METH Fab on METH toxicity will be studied in dogs at toxic doses in preparation for scaling up the therapy to humans. These integrated studies of pharmacokinetic, behavioral and neurochemical changes after antibody-based therapy will serve as a prototypic model that can be applied to treating the effects of other drugs of abuse.